International patent applications including WO 03/029232 and WO 2007/144005 disclose the compound 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and pharmaceutically acceptable salts thereof. WHO has since published that vortioxetine is the recommended International Non-proprietary Name (INN) for 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine. Vortioxetine was formerly referred to in the literature as LU AA21004. In September 2013 FDA approved vortioxetine for the treatment of major depressive disorder under the trade name Brintellix™.
Vortioxetine is an antagonist on the 5-HT3, 5-HT7 and 5-HT1D receptors, an agonist on the 5-HT1A receptor and a partial agonist on the 5-HT1B receptor and an inhibitor of the serotonin transporter. Additionally, vortioxetine has demonstrated to enhance the levels of the neurotransmitters serotonin, noradrenalin, dopamine, acetylcholine and histamine in specific areas of the brain. All of these activities are considered to be of clinical relevance and potentially involved in the mechanism of action of the compound [J. Med. Chem., 54, 3206-3221, 2011; Eur. Neuropshycopharmacol., 18(suppl 4), S321, 2008; Eur. Neuropshycopharmacol., 21(suppl 4), S407-408, 2011; Int. J. Psychiatry Clin Pract. 5, 47, 2012].
Vortioxetine has in clinical trials shown to be a safe and efficacious treatment for depression. A paper reporting the results from a proof-of-concept study to evaluate the efficacy and tolerability of the compound in patients with major depressive disorder (MDD) authored by Alvares et al was made available on-line by Int. J. Neuropsychopharm. 18 Jul. 2011. The results from the six weeks, randomised, placebo-controlled study with approximately 100 patients in each arm show that vortioxetine separates significantly from placebo in the treatment of depressive and anxious symptoms in patients with MDD. It is also reported that no clinically relevant changes were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. Results from a long-term study also show that vortioxetine is effective in preventing relapse in patients suffering from MDD [Eur. Neuropsychopharmacol. 21(suppl 3), S396-397, 2011]. A study in elderly depressed patients reported in Int. Clin. Psychopharm., 27, 215-227, 2012 shows that vortioxetine may be used to treat cognitive dysfunctions.
The International application published as WO 2009/062517 discloses that vortioxetine may be combined with other types of pharmaceutically active ingredients, such as interferones, opiates, ACE inhibitors and acetylcholine esterase inhibitors.
The impact that serotonin levels and activation or inhibition of serotonin receptors may have on acetylcholine levels has been extensively reviewed—see Pharmacol Rev, 59, 360-417, 2007. It emerges from this review that the influence of the serotonergic system on acetylcholine release is extremely complicated and far from understood.
Acetylcholine is a neurotransmitter that acts in the central as well as peripheral nervous system. A low level of acetylcholine has been associated with diseases in which cognitive dysfunction plays a significant role, such as Alzheimer's disease. In fact, administration of acetylcholine esterase inhibitors is one of the two major treatment paradigms for Alzheimer's disease. The other major treatment paradigm is the administration of memantine, an NMDA receptor antagonist. Three acetylcholine esterase inhibitors are presently approved for treatment of Alzheimer's disease, i.e. donepezil, rivastigmine and galantamine. Donepezil was first approved by FDA in 1996; Rivastigmine was first approved by FDA in 2000; and Galantamine was first approved by FDA in 2001.
In addition to the three above mentioned acetylcholine esterase inhibitors, the compound tacrine was previously approved by FDA. Furthermore, the patent literature contains a long range of documents disclosing compounds that act as acetylcholine esterase inhibitors, examples of which include WO 88/08708, WO 93/13100, WO97/38993, WO 2003/082820, U.S. Pat. No. 4,914,102, U.S. Pat. No. 5,231,093, U.S. Pat. No. 5,246,947, EP 268871, EP 298202, EP 409676, EP477903 and EP 703901.
Cognitive dysfunction plays a major role in many CNS (Central Nervous System) diseases. This includes for instance Alzheimer's disease, vascular dementia, and cognitive dysfunction associated with depression, schizophrenia, Parkinson's disease, abuse or Huntington's disease. Cognitive dysfunction is not adequately addressed with current therapy and the present invention seeks to provide alternative and more efficient ways to treat cognitive dysfunction.